Humans have a significantly higher resistance to aging than any other mammalian species. Our general research objective has been to understand the biological basis of this resistance. The research program involves three inter-related projects, entitled: (1) Stability of Proper Gene Expression, (2) Mechanisms Causing Improper Gene Expression and (3) Stabilizing Mechanisms of Proper Gene Expression. Past work involving the first two projects has found evidence that proper gene expression is not maintained with increasing age of an animal. The mechanism causing this improper gene expression may involve specific types of chromatin alterations, as evidenced by our findings of altered chromatin physiochemical properties. Recent work has centered on the third project, the mechanisms stabilizing proper gene expression. We have been examining the possibility that normal tissue antioxidants may help to stabilize the differentiated state of cells and may therefore be important determinants of human longevity. These antioxidants include superoxide dismutase, urate, alpha tocopherol, and the carotenoids, which show a good positive correlation with maximum life span potential of mammalian species. However, no correlation was found for ascorbate, and a negative correlation was found for glutathione, glutathione peroxidase, glutathione S-transferase and catalase, indicating that these enzymes may have toxic side effects previously not recognized. The rate of tissue homogenates autoxidizing in air, forming lipid peroxides, has been found to be inversely related to the maximum lifespan potentials of a number of different mammalian species. Taken together, these results indicate that aging is a result of cellular dysdifferentiation and that specific antioxidants and the structural composition of cells determine net sensitivity of tissue to the toxic effects of oxygen radicals and consequently the stability of cells against dysdifferentiation. Thus, longer-lived species have, in proportion to their longevity, more of these protective mechanisms which could appear to act importantly in stabilizing proper gene expression.